Acid- and base-catalyzed hydrolysis of chloroacetamide herbicides

Article abstract of DOI:10.1021/jf0530704

Despite the prevalence of chloroacetamides as herbicides, little is known about the rates or products of acid- or base-catalyzed hydrolysis of these compounds. Mechanisms of acid-catalyzed reactions may parallel those catalyzed by (hydr)oxide minerals, while base-catalyzed processes have as important counterparts reactions with environmental nucleophiles (such as reduced sulfur species). The current study systematically investigates how the structure of nine chloroacetamides affects their reactivity in 2 N NaOH, 2 N HCl, or 6 N HCl at 25 or 85°C. Base-catalyzed hydrolysis proceeds either through an intermolecular S_N2 reaction to hydroxy-substituted derivatives or (in a few cases) through amide cleavage, while both amide and ether group cleavages are observed under acidic conditions. Our results reveal that subtle differences in chloroacetamide structure [notably the type of (alkoxy)alkyl substituent] can dramatically influence reactivity and reaction mechanism. Hydroxy-substituted, morpholinone, and secondary aniline derivatives were identified upon reaction for several years in deionized water at circumneutral pH.

Full text of DOI:10.1021/jf0530704

4740 J. Agric. Food Chem. 2006, 54, 4740−4750
Acid- and Base-Catalyzed Hydrolysis of Chloroacetamide
Herbicides
DANIEL L. CARLSON, KHOI D. THAN, AND A. LYNN ROBERTS*
Department of Geography and Environmental Engineering, Johns Hopkins University, 313 Ames Hall,
3400 North Charles Street, Baltimore, Maryland 21218-2686
Despite the prevalence of chloroacetamides as herbicides, little is known about the rates or products
of acid- or base-catalyzed hydrolysis of these compounds. Mechanisms of acid-catalyzed reactions
may parallel those catalyzed by (hydr)oxide minerals, while base-catalyzed processes have as
important counterparts reactions with environmental nucleophiles (such as reduced sulfur species).
The current study systematically investigates how the structure of nine chloroacetamides affects their
reactivity in 2 N NaOH, 2 N HCl, or 6 N HCl at 25 or 85 °C. Base-catalyzed hydrolysis proceeds
either through an intermolecular SN2 reaction to hydroxy-substituted derivatives or (in a few cases)
through amide cleavage, while both amide and ether group cleavages are observed under acidic
conditions. Our results reveal that subtle differences in chloroacetamide structure [notably the type
of (alkoxy)alkyl substituent] can dramatically influence reactivity and reaction mechanism. Hydroxy-
substituted, morpholinone, and secondary aniline derivatives were identified upon reaction for several
years in deionized water at circumneutral pH.
KEYWORDS: Herbicide degradates; chloroacetanilides; acetochlor; alachlor; butachlor; dimethachlor;
dimethenamid; pretilachlor; propachlor; metolachlor
INTRODUCTION
environmentally relevant conditions (Table 1) is still scarce in
the peer-reviewed literature (6-15). Published half-lives (1-7
years) are generally substantially greater than the duration of
most investigations (6, 7). Products of hydrolysis reactions have
been identified for the N-alkoxymethyl-substituted chloroac-
etamides butachlor (8, 11) and propisochlor (9); both N-
dealkylation and chlorine substitution products have been
reported (Table 1). Additional studies not included in Table 1
have examined other reactions under more strongly acidic
conditions. These include ones in which the alkoxymethyl
substituent is cleaved, as observed for alachlor in 5 N HCl/
acetone at 46 °C (16), and a unique intramolecular ether
hydrolysis reaction, as reported for metolachlor at elevated
temperatures and HCl concentrations (17, 18).
Chloroacetamides represent one of the most widely used
classes of herbicides in the United States (1). Within this broad
class, the popularity of some compounds, such as alachlor, has
waned in recent years, while the use of others, such as acetochlor
and dimethenamid, is increasing. Although such changes have
been shown to be reflected in the relative concentrations of
parent herbicides in environmental samples (2), little information
exists pertaining to the influence of variations in chloroacetamide
structure on reactivity and, hence, environmental persistence.
At present, we are unable to anticipate how the structure of the
parent chloroacetamide compound will affect the different types
of products that will result from transformations of these
herbicides in the environment.
Studies of both acid- and base-catalyzed hydrolysis of
chloroacetamides may provide valuable information regarding
other environmental reactions that involve similar mechanisms.
Metal ionsseither in solution or present as components of
(hydr)oxide mineral surfacessmay be able to facilitate hydroly-
sis by acting as Lewis acids, coordinating the oxygen of either
the amide (19) or the N-alkoxyalkyl group (if present). Indeed,
enhanced hydrolysis of tertiary amides has been observed
previously in the presence of copper, cobalt, and zinc ions (20,
21). In addition, an improved understanding of the base-
catalyzed reactions of chloroacetamides could provide insights
into environmental and metabolically relevant interactions
between these herbicides and various nucleophiles, such as
reduced sulfur species (14, 22, 23).
Perhaps the most fundamental environmental reaction is
hydrolysis. Although chloroacetamides can readily undergo
photolysis and biotransformation (3), there are environments
where these processes are negligible and slower reactions may
predominate. Ex situ degradation studies in the presence of
aquifer materials have reported disappearance half-lives of 1-5
years for these compounds (4, 5). Under such conditions,
hydrolysis may represent an important process in controlling
chloroacetamide fate in the environment. Despite years of
research on the environmental fate of these herbicides, informa-
tion pertaining to the rates of chloroacetamide hydrolysis under
* To whom correspondence should be addressed. Tel: 410-516-4387.
Fax: 410-516-8996. E-mail: lroberts@jhu.edu.
10.1021/jf0530704 CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/07/2006

Hydrolysis of Chloroacetamide Herbicides
J. Agric. Food Chem., Vol. 54, No. 13, 2006 4741
Table 1. Literature Data Pertaining to Chloroacetamide Hydrolysis
-
1
herbicide
propachlor
T (
°
C)
pH
rate constant (days
)
t1 2 (days)
time (days)a
products observed
hydroxybutachlor
ref
/
-
-
-
3
3
4
25
5
7
9
4
2.2
1.2
7.8
×
×
×
×
×
10
10
10
10
10
320
600
890
1400
2300
630
1200
4.4
160
160
160
130
130
130
130
NAe
NAe
NAe
NAe
103
6
-
-
4
acetochlor
butachlor
25
25
70
5
3
7
4
7, 10
-
3
4
1.1
×
×
10
10
7, 8
9
-
4
7, 10
2
11
7
6
-2
-2
-1
-1
propisochlor
1.6
4.1
3.6
4.3
×
×
×
×
10
10
10
10
N-dealkylation product
hydroxypropisochlor
1.6
19
17
dimethachlor
pretilachlor
butachlor
70
70
b
10
10
11
7
1
−10
no degradation observed
N-dealkylation product
at pH 1 (trace)
metolachlor
alachlor
20
b
4, 7, 9
5
7
<5% degradation
100
140
140
140
NAe
12
13
-
-
-
2
2
2
3.6
3.5
3.2
×
×
×
10
10
10
19
20
22
>100
8
metolachlor, acetochlor,
propachlor, and alachlor
propachlor
20
d
H2Oc
<0.01
14
15
-
-1
1−3
0.147 (M 1 h
)
NAe
a Duration over which the reaction was monitored. b Room temperature (23
e Information not provided in original source.
−27
°
C). c Deionized water. d Extrapolated to room temperature from high-temperature experiments.
Knowledge regarding the products of hydrolysis reactions,
as well as their toxicity relative to that of their parent
compounds, is needed in order to assess the effects of chloro-
acetamide usage on human health and the environment. As a
result of concerns regarding the toxicity of chloroacetamides,
the U.S. EPA has established drinking water standards for
alachlor (24). Regulations for metolachlor in drinking water are
reportedly under consideration (25). Some hydrolysis products,
such as the chloroacetamide formed from the N-dealkylation
of alachlor and butachlor, have been found to be mutagenic
and may bind to DNA (26). Indeed, the primary aniline
degradates of alachlor and metolachlor are both teratogenic, and
in the case of metolachlor, the degradate has been reported to
be less cytotoxic but more teratogenic than the parent (27). In
some cases, however, hydroxy-substituted products have been
found to be either not mutagenic (26), less mutagenic (15), or
less phytotoxic (28) than their respective parents. In part because
of such toxicity concerns, the U.S. EPA has included acetanilide
pesticide degradation products, as well as additional chloroac-
etamide herbicides, on the second Contaminant Candidate List
of substances that may be regulated in the future (29).
In this research, we systematically evaluated the hydrolysis
of chloroacetamide herbicides under both acidic (2 N HCl) and
basic (2 N NaOH) conditions at 25 °C, in addition to conducting
a more limited range of experiments in 6 N HCl at 85 °C.
Experiments in sterile deionized water were also carried out
over the course of 2-3 years to ascertain whether products
encountered at circumneutral pH were the same as those
measured under more extreme conditions. While the departure
from environmentally relevant conditions in most of the
experiments lessens the direct applicability of our results, it
allows us to compare the reactivity of a suite of chloroacetamide
herbicides (Figure 1) both quantitatively and qualitatively on
an experimentally accessible time scale. The results further allow
us to explore the effect of structural modifications on reaction
pathways and hydrolytic reactivity (and, by extension, reaction
with metal ions and environmental nucleophiles); this informa-
tion furnishes a more complete understanding of the behavior
of chloroacetamide herbicides in environmental systems.
Figure 1. Structures of chloroacetamides examined in this study. All except
for 2-chloro-N-methylacetanilide, herein referred to as methylchlor, are
commercial herbicides.
MATERIALS AND METHODS
Chemicals. Acetochlor [2-chloro-2′-ethyl-6′-methyl-N-(ethoxy-
methyl)acetanilide; 99%], alachlor [2-chloro-2′,6′-diethyl-N-(methoxy-
methyl)acetanilide; 99%], butachlor [2-chloro-2′,6′-diethyl-N-(butoxy-
methyl)acetanilide; 99%], metolachlor [2-chloro-2′-ethyl-6′-methyl-N-
(1-methyl-2-methoxyethyl)acetanilide; 99%], propachlor [2-chloro-N-
isopropylacetanilide; 99.5%], and 2-ethyl-6-methyl-N-(1-hydroxypropan-
2-yl)aniline (an amino alcohol degradate of metolachlor, 99%) were
obtained from Chem Service (West Chester, PA). Dimethachlor
[2-chloro-2′,6′-dimethyl-N-(methoxyethyl)acetanilide; 99.8%], dimeth-
enamid [2-chloro-N-(1-methyl-2-methoxyethyl)-N-(2,4-dimethyl-thien-
3-yl)acetamide; 99.9%], pretilachlor [2-chloro-2′,6′-diethyl-N-(pro-
poxyethyl)acetanilide; 98.3%], 2-chloro-N-phenyl-N-methyl-acetamide,
N-isopropylaniline (99%), N-methylaniline (99.5%), 2-ethyl-6-methyl-

4742 J. Agric. Food Chem., Vol. 54, No. 13, 2006
Carlson et al.
aniline (99%), and 2-nitro-m-xylene (99%) were obtained from Sigma-
Aldrich (Milwaukee, WI). HCl (2.0 and 6.0 N) and NaOH (2.0 N)
were obtained from Fisher Scientific.
Scheme 1
Several potential hydrolysis products were synthesized during the
course of this and related studies. These include the metolachlor
derivatives 2-chloro-N-(2-ethyl-6-methyl)-N-(1-hydroxypropan-2-yl)-
acetamide; 4-(2-ethyl-6-methylphenyl)-5-methyl-3-morpholinone; 2-chlo-
ro-N-(2-ethyl-6-methylphenyl)acetamide (also a potential acetochlor
degradate); and 2-chloro-N-(2,6-diethylphenyl)acetamide, a potential
degradate of butachlor, alachlor, and pretilachlor. Synthesis of these
compounds is described by Hladik et al. (30). Two other hydrolysis
products synthesized for this study are the metolachlor degradation
product 2-ethyl-6-methyl-N-isopropylideneaniline and the propachlor
derivative 2-hydroxy-N-phenyl-N-isopropyl-acetamide. Methods used
to synthesize these compounds are provided in the Supporting Informa-
1
tion, along with mass and H NMR spectral data.
and a 30 m J&W DB-5 or Restek Rtx-5, 0.25 mm i.d. × 0.25 µm
fused silica capillary column or a Carlo-Erba Mega 2 GC equipped
with an on-column injector, a flameless nitrogen phosphorus detector,
and a 30 m DB-5 J&W, 0.25 mm i.d. × 0.25 µm fused silica capillary
column. The EI mass spectra were generated using an electron energy
of 70 eV; data were acquired in full scan mode (m/z 65-550).
Data Analysis. Rate constants were calculated by regressing the
natural logarithm of the parent chloroacetamide concentration against
time, using at least seven data points for each kinetic run. Statistical
analyses showed R2 > 0.990 in all cases, with R2 > 0.998 for the
majority of the experiments. No trends in the residuals were evident
that might be indicative of deviation from pseudo-first-order reaction.
In cases where products were quantified, the software package Scientist
(Micromath) was used to model parent compound disappearance and
product appearance simultaneously, by either assuming exponential
decay to a single product or concurrent transformation of one parent
compound to two stable products, as appropriate.
18O-labeled water (95%) was obtained from Isotec, Inc. (Miamisburg,
OH). 18O-labeled solutions were generated by passing a stream of
purified N2 gas through concentrated aqueous HCl (∼12 N) and H218O
(to form 2.3 N HCl, as estimated by titration) or by diluting this solution
with concentrated aqueous HCl (to form 6.0 N HCl). The maximum
extent of 18O label incorporation into the reaction products in the 2.3
and 6.0 N HCl solutions (∼75 and ∼35%, respectively) corresponded
closely to the gravimetric estimates of 18O content in the two solutions.
Experimental Systems. Reactions were carried out in amber glass
bottles maintained in the dark in a water bath with an accuracy of (0.25
°C and a temperature stability of (0.05 °C. Aliquots (1.00 mL) of
reaction solution were periodically removed and extracted with 1.00
mL of n-hexane containing nitroxylene as an internal standard. For
acid-catalyzed reactions of 2-chloro-N-phenyl-N-methyl-acetamide
(methylchlor), propachlor, alachlor, and metolachlor and for base-
catalyzed reactions of methylchlor and propachlor, products were
synthesized or commercially purchased to allow for quantification; all
other chloroacetamide reaction products were identified by their electron
ionization (EI) mass spectra. Extraction efficiencies of parent com-
pounds were between 71 and 103%, while those of products for which
authentic reference materials were available ranged between 79 and
101%.
Reactions in 2 N HCl or 2 N NaOH were conducted at a temperature
of 25.0 °C. Chloroacetamides were introduced in these experiments
by adding 0.50 mL of a saturated aqueous solution of the compound
in question, resulting in a final concentration of 1.96 N HCl or NaOH.
Aqueous spikes were used to avoid side reactions with a carrier solvent;
preliminary experiments in NaOH solutions revealed substitution by
methoxide when a methanolic spike was used and formation of
unidentified (and unanticipated) products when an acetone spike was
used. For some samples from the reactions in 2 N HCl, 1.00 mL aliquots
were neutralized by adding 0.172 g of NaHCO3 prior to extraction, to
facilitate product identification and quantification.
RESULTS AND DISCUSSION
Reactions in 2 N HCl at 25 °C. The chloroacetamides shown
in Figure 1 can be divided into three groups based on whether
they contain an N-alkyl, N-alkoxymethyl, or an N-alkoxyethyl
substituent. Each group reacted by very different pathways under
acidic conditions. The two compounds possessing N-alkyl
substituents, propachlor and 2-chloro-N-phenyl-N-methyl-ac-
etamide (hereafter referred to as methylchlor for convenience),
reacted solely through a well-recognized (32) AAC2 (acid-
catalyzed acyl cleavage, bimolecular) amide hydrolysis mech-
anism (Scheme 1) in 1.96 N HCl at 25 °C, as inferred from
product yields (Figure 2a). Rate constants for these reactions
are shown in Table 2.
The three compounds possessing N-alkoxymethyl substituents
reacted at roughly similar rates (Table 2), presumably through
an initial ether hydrolysis step (Scheme 2) to form the
N-dealkylation products (mass spectra are shown as Figure S1
in the Supporting Information). An example time course,
showing the disappearance of alachlor and the appearance of
its N-dealkylation product, is provided in Figure 2b. N-
Dealkylation appeared to be followed by very slow hydrolysis
of the amide linkage, as suggested by the observation of small
amounts of primary anilines (identified by GC/MS) in neutral-
ized reaction solutions after several months. Dealkylation of
alachlor and butachlor to 2-chloro-N-(2,6-diethylphenyl)aceta-
mide has been observed previously (9, 11, 16), but a mechanism
does not appear to have been proposed for chloroacetamides.
Our hypothesized mechanism (Scheme 2) involves an initial
protonation of the ether oxygen, followed by the formation of
a Schiff base intermediate (center, Scheme 2). The Schiff base
would rapidly hydrolyze to form the observed secondary aniline.
Such a mechanism was first proposed in 1932 for the transfor-
mation of dialkylaminomethyl ethers in aqueous acidic solution
at room temperature (33). A similar mechanism has been
For reactions in 6 N HCl at 85 °C, smaller (0.10 mL) spikes were
used, to minimize perturbations of reactor temperature. Methanol was
used as a carrier in such cases to attain the desired initial concentrations.
Preliminary experiments showed no effect on rates or product distribu-
tion from the presence of the methanol. Samples were removed through
an exterior valve attached to a Teflon needle inside the bottle. The
reaction was quenched by cooling the sample vials in water. For some
samples, 1.00 mL aliquots were neutralized by adding 0.515 g of
NaHCO3 prior to extraction. The rationale for this neutralization
procedure is provided below.
Long-term experiments were carried out in unbuffered deionized,
UV- and filter-sterilized (0.2 µm) water (pH between 5 and 6)
equilibrated for several days with solid or liquid chloroacetamide. The
supernatant solution was removed and transferred to bottles that had
been baked in a muffle furnace (400 °C) prior to use; caps were not
sterilized. The solutions were tightly sealed and stored in the dark, and
the temperature was not controlled. Sterility (<104 cells/mL, the same
as distilled, deionized, filtered, and UV-irradiated water) was confirmed
at the end of the reaction using the acridine orange method (31).
Gas Chromatography (GC) and GC/Mass Spectrometry (MS)
Analyses. The hexane extracts were analyzed using a Thermo Finnigan
Trace quadrupole GC/MS system equipped with an on-column injector

Hydrolysis of Chloroacetamide Herbicides
J. Agric. Food Chem., Vol. 54, No. 13, 2006 4743
in 1.96 N HCl at 25 °C (Table 2) were estimated from the rates
of appearance of the products and disappearance of the parent
compounds over a period of 297 days. As the shortest half-life
estimate from these experiments was greater than 200 days, these
conditions were clearly not suitable for obtaining precise rate
measurements.
Reaction of Metolachlor in 6 N HCl at 85 °C. The
mechanism of the acid hydrolysis of metolachlor was studied
in greater detail under more highly acidic conditions and at a
higher temperature. Figure 2c shows the results from a series
of short-term experiments for this compound. Under these
conditions, a complex set of reactions (Scheme 3) beginning
with an intramolecular attack by the ether oxygen on the amide
(Scheme 4) appears to have occurred. [Schemes 3 and 4 are
based on our work and that of Arcelli et al. (17, 35-39) with
metolachlor and related compounds.] Figure 3 shows the time
courses (on a logarithmic scale) for the disappearance of
metolachlor and the appearance of its degradates over a period
of 2 weeks. Our results are consistent with the previous studies,
with one exception: Arcelli et al. (17) suggested, in the case
of metolachlor, that 3 and 4 are formed from 1 through two
parallel reactions involving the ether oxygen, one involving
nucleophilic acyl addition at the carbonyl to form 3, and the
second involving intramolecular SN2 cyclization to form 4. Our
results, however (Figure 3), indicate that substantial amounts
of 4 do not appear until most of the metolachlor (1) has reacted.
This observation suggests that 4 only forms indirectly via 2 and
3, implying that dual assistance by the ether oxygen does not
occur. Arcelli et al. had observed both 3 and 4 following
neutralization of the acidic solution by NaOH. Our methods, in
contrast, use NaHCO3 for neutralization. We were able to
reproduce their results by neutralizing with NaOH and, therefore,
suspect that imperfect mixing and the generation of substantial
amounts of heat during neutralization with NaOH resulted in
the rapid production of 4sthereby obscuring the transient
appearance of 2 and 3sduring the experiments conducted by
Arcelli et al. For this reason, only NaHCO3 was used for
neutralization in this work. During neutralization with NaHCO3,
2 was consistently found to be transformed (with yields of more
than 98% on the basis of peak areas) into 3, which was initially
absent. Therefore, the alcohol 3 can be used as a surrogate for
2 in Figure 3.
Labeling experiments were used to further explore the
formation of the morpholinone derivative (4) by tracking the
origin of the oxygen atoms in the positions corresponding to
the ether (oxygen A, Scheme 3) and amide (oxygen B) groups
in metolachlor. Oxygen B in compound 3 (and by inference 2)
acquired 70% 18O after reaction in 18O-labeled 2.3 N HCl
solution for 1 h at 75 °C. The unreacted metolachlor did not
acquire a label on either of its oxygens. When the extract with
labeled compound 3 was subsequently added to unlabeled 6.0
N HCl and the hexane was evaporated, the label on oxygen B
was lost after incubating the solution for 1 h at 85 °C. This
confirms that oxygen B in compound 3 is labile under acidic
conditions (35).
Figure 2. Example time courses for acid hydrolysis: (a) methylchlor (
9
)
in 2 N HCl at 25
°
C, (b) alachlor (
b) in 2 N HCl at 25
°
C, and (c)
metolachlor ( ) in 6 N HCl at 85
[
°
C. Dashed lines and triangles (2
)
represent mass balances on parent compounds and products shown, solid
lines represent model fits assuming pseudo-first-order transformation to
a single stable product, and error bars represent 95% confidence intervals.
Longer term labeling experiments showed that oxygen A in
compounds 2 and 3 acquired up to 34% 18O after reaction in
18O-labeled 6.0 N HCl solution for 2 days at 85 °C. When the
extract with labeled compounds 2 and 3 was subsequently added
to unlabeled 6.0 N HCl and the hexane was evaporated, 30%
of the label on oxygen A was removed after incubating the
solution for 1 h at 85 °C. This indicates that, surprisingly,
oxygen A is also relatively labile, although not as labile as
oxygen B. The morpholinone 4 also showed full labeling of
proposed for the loss of an N-methoxymethyl group from a
tertiary aniline in basic methanol (34), the main difference being
in the degree of protonation of the ether oxygen and, hence,
the leaving group.
The remaining chloroacetamides, possessing an N-alkoxyethyl
moiety, were substantially more recalcitrant toward reaction in
acidic solution. Reactions of these compounds primarily ap-
peared, at least initially, to involve conversion of the ether side
chain to the corresponding alcohol. Rate constants for reaction

4744 J. Agric. Food Chem., Vol. 54, No. 13, 2006
Carlson et al.
Table 2. Observed Pseudo-First-Order Rate Constants for Chloroacetamide Hydrolysisa
-1
kobs (s
)
1.96 N NaOH, 25
°
C
1.96 N NaOH, 25
SN2b
°C
chloroacetamide
1.96 N HCl, 25
°
C
6.0 N HCl, 85
°
C
amide hydrolysisb
N-alkyl substituted
methylchlor
propachlor
-
7
7
-
2
8.44 (
1.09 (
±
±
0.56)
0.09)
×
×
10
1.44 (
2.51 (
±
±
0.04)
0.67)
×
×
10
10
-
-6
-5
10
9.39 (±
0.38)
×
10
N-alkoxymethyl substituted
alachlor
acetochlor
-
-
-
6
6
6
-5
-5
-5
2.45 (
2.72 (
1.93 (
±
±
±
0.06)
0.18)
0.07)
×
×
×
10
10
10
2.95 (
3.06 (
3.04 (
±
±
±
0.17)
0.09)
0.32)
×
×
×
10
10
10
butachhlor
N-alkoxyethyl substituted
pretilachlor
dimethachlor
dimethenamid
metolachlor
-
10
-
10c
-5
-5
-4
-4
-5
-5
-6
-6
2
×
10
−
4
×
10
6.22 (
3.77 (
3.39 (
7.25 (
±
±
±
±
0.23)
0.30)
0.29)
0.26)
×
×
×
×
10
10
10
10
2.22 (
1.79 (
6.77 (
3.83 (
±
±
±
±
0.10)
0.02)
0.35)
0.12)
×
×
×
×
10
10
10
10
NAd
-
-
9
-8c
5
9
×
×
10
10
−
−2 ×
4
×
10
10
9
-8c
a Stated uncertainties represent 95% confidence limits except as noted; rate constants may represent more than one mechanism and should not be extrapolated.
b Mechanism assigned based on observed products. c Reflects range of estimates, not confidence limits. d NA, not available; as results under these conditions were not
promising for the other N-alkoxyethyl-substituted chloroacetamides, the relevant experiments with dimethachlor were not performed.
acetamide (8, Figures 3 and S2). At high temperatures and under
strongly acidic conditions, therefore, metolachlor can be trans-
formed into its primary aniline degradate (6), albeit slowly.
Hydrolysis of Pretilachlor, Dimethachlor, and Dimeth-
enamid in 6 N HCl at 85 °C. More limited studies were carried
out to examine the acid hydrolysis of the other N-alkoxyethyl-
substituted chloroacetamides at elevated temperature in 6 N HCl.
The resulting rate constants are shown in Table 2. For
pretilachlor and dimethachlor, the end products were the primary
anilines and the morpholinone derivatives. Mass spectra of the
observed products are shown in Figures S3-S8 of the Sup-
porting Information. The thienyl-based herbicide dimethenamid
reacted differently under acidic conditions, forming what
appeared to be several unidentified polymers (as determined
by GC/MS). These products would be consistent with prior
observations of the polymerization of thiophene at high tem-
peratures and highly acidic conditions (41).
Substituent Effects on Reactions of Chloroacetamides in
Acid Solution. Among the chloroacetamides studied, substit-
uents affect reactions in acidic solution in multiple ways. For
example, relatively rapid reaction occurs under acidic conditions
if an N-alkoxymethyl substituent is present, while reactivity
under comparable conditions is somewhat depressed for N-alkyl-
substituted chloroacetamides and is greatly depressed for
N-alkoxyethyl-substituted chloroacetamides (Table 2).
Within a particular group of chloroacetamides, minor varia-
tions in reactivity can often be attributed to steric effects. For
example, the slower reactivity of propachlor relative to meth-
ylchlor (Table 2) can be rationalized on this basis. A comparison
of their structures (Figure 1) suggests that increasing the steric
hindrance of the N-alkyl substituent slows the rate of attack by
H2O during the AAC2 reaction (Scheme 1).
Subtle structural differences within a group can result in
substantial differences in reactivity. For example, even among
the alkoxyethyl-substituted chloroacetamides, the data in Table
2 reveal reactivity differences of more than an order of
magnitude. The lower reactivity of pretilachlor as compared to
metolachlor or dimethenamid could reflect greater steric hin-
drance in the initial attack by the ether oxygen at the carbonyl
(Scheme 3) that the bulkier propyl substituent would provide
relative to the methyl substituent in the other two compounds.
However, this effect alone does not explain why dimethachlors
with less steric hindrance than pretilachlorsreacts more slowly
still. Influences other than steric effects also appear to be
responsible for the fact that metolachlor (which, as compared
Scheme 2
oxygen A, supporting its formation from the intermediate 3
rather than via nucleophilic attack by the ether oxygen. (Had
the latter been the case, 4 would not have been expected to
acquire any of the 18O label during this experiment, given that
18O was not observed to be incorporated into metolachlor itself).
As was observed for metolachlor (1), no significant change in
the label was observed following incubation of labeled 4 in
unlabeled solution.
The morpholinone derivative was not the only compound
produced from the reaction of metolachlor in 6 N HCl at 85
°C. Figure 3 shows that the major product at the end of 2 weeks
(∼24000 min) was the amino alcohol (5), which we infer is
formed via hydrolysis of an aminoester {chloromethyl-2-[N-
(2-ethyl-6-methylphenyl)amino]propyl-carboxylate}, as reported
for analogous compounds (35, 36). Figure S2 in the Supporting
Information expands the pathways depicted in Scheme 3. The
amino alcohol (5) reacts via a series of intermediates, of which
the Schiff base (2-ethyl-6-methyl-N-isopropylidene aniline, 7,
Figure S2) was observed in trace amounts, to form the primary
aniline 2-ethyl-6-methylaniline (6, Figure 3). Dehydration of
the amino alcohol (5) might then be expected to form an
enamine intermediate. The enamine would be in equilibrium
with the imine (Schiff base, 7), an equilibrium that is thought
to strongly favor the imine form (40). The Schiff base can easily
hydrolyze to form 2-ethyl-6-methylaniline (6), a reaction that
was observed in separate experiments with 2-ethyl-6-methyl-
N-isopropylidene aniline as the starting material. We speculate
that the Schiff base (7), as well as the resulting primary aniline
(6), could also be formed earlier in the reaction sequence by
elimination of chloroacetic acid from the aminoester {chloro-
methyl-2-[N-(2-ethyl-6-methylphenyl)amino]propylcarboxylate}
or amide hydrolysis of 2-chloro-N-(2-ethyl-6-methylphenyl)-

Hydrolysis of Chloroacetamide Herbicides
J. Agric. Food Chem., Vol. 54, No. 13, 2006 4745
Scheme 3
Scheme 4a
exception being dimethenamid). N-Dealkylation followed by
slow amide hydrolysis was observed for the N-alkoxymethyl-
substituted chloroacetamides, while a complex sequence of
reactions (Figure S2) led to the primary anilines for those
chloroacetamides possessing N-alkoxyethyl substituents.
The different chloroacetamides evinced interesting differences
in the rates of reaction at their common chloroacetamide
functional group under acidic conditions. At 25 °C, the
hydrolysis of the amide linkage was observed to occur on a
time scale of days for methylchlor, weeks for propachlor, and
months to years for the N-dealkylation products of alachlor and
butachlor [2-chloro-N-(2,6-diethylphenyl)acetamide] and ac-
etochlor [2-chloro-N-(2-ethyl-6-methylphenyl)acetamide], while
the reaction was too slow to measure for metolachlor (at 25
°C). Contrasts in steric hindrance provide at least a partial
explanation for these observations. Thus, while the bulkier
N-isopropyl group may have slowed the hydrolysis reaction
more for propachlor than did the N-methyl group of methylchlor
(a pattern also observed under basic conditions, as described in
the next section), even greater steric hindrance by the ortho
substituents on the aromatic ring of the product of alachlor
N-dealkylation [2-chloro-N-(2,6-diethylphenyl)acetamide] may
contribute to the observation that the latter compound does not
react appreciably under the same conditions (as shown by the
relatively consistent mass balance in Figure 2b).
a Adapted from ref 17. The structure on the right has a delocalized positive
charge with a proton in an unknown location.
Electronic effects may also be responsible for some of these
observed relations between structure and reactivity. Methylchlor
and propachlor also have an alkyl substituent on the amide
nitrogen in place of the hydrogen of 2-chloro-N-(2,6-dieth-
ylphenyl)acetamide, and this could also play a role in the
reactivity of the amide group. Biechler and Taft (42), for
example, have found that 2,2,2-trifluoro-N-methyl-N-phenyl-
acetamide underwent amide hydrolysis faster than 2,2,2-
trifluoro-N-phenyl-acetamide under basic conditions. They
suggested that the rate-enhancing effect of an N-methyl group
might stem from its inhibition of amide resonance, which would
also occur under our acidic conditions. This effect could help
explain the faster rates of amide hydrolysis observed for
methylchlor and propachlor, relative to 2-chloro-N-(2,6-dieth-
ylphenyl)acetamide and 2-chloro-N-(2-ethyl-6-methylphenyl)-
acetamide. Unfortunately, we lack data for the acid hydrolysis
of the amide linkage of 2-chloro-N-acetamide, which might help
in clarifying whether steric hindrance to attack of the amide
group introduced by ortho substituents on the ring or resonance
inhibition by the N-alkyl substituent better accounts for the
reactivity trends that we observed.
Figure 3. Reaction time course for metolachlor in 6 N HCl at 85 °C,
analyzed upon neutralization with NaHCO3 and extraction into hexane.
Note the log scale on both axes. Concentrations of intermediates were
estimated from mass response on GC/MS analysis of hexane extracts;
model fits were performed assuming pseudo-first-order conditions for
reactions shown in Scheme 3 and Figure S2. Key: 1, metolachlor (
3, formed from 2 during neutralization ( ); 4, morpholinone derivative
); aminoester, chloromethyl-2-[N-(2-ethyl-6-methylphenyl)amino]propyl-
carboxylate ( ); 5, amino alcohol ( ); 6, 2-ethyl-6-methylaniline ( );
2-chloro-N-(2-ethyl-6-methylphenyl)acetamide present as an impurity in
metolachlor initially but also formed during reaction ( ). Concentrations
[);
0
(]
9
2
O
s
b
of the aminoester were estimated based on the mass response of other
chloroacetamide derivatives, as no authentic standard was available.
to dimethachlor, has methyl groups replacing two hydrogen
atoms) reacts in 6.0 N HCl nearly 20 times faster than
dimethachlor.
Substituents affect not only reactivity and the initial products
formed in acid solution but also the final products. N-
Dealkylation was not observed for the alkyl-substituted com-
pounds propachlor and methylchlor even after several months.
In contrast, the formation of primary anilines was observed for
six of the seven N-alkoxyalkyl-substituted chloroacetamides (the
Reactions in Basic Solution. Two types of reaction were
observed in 1.96 N NaOH at 25 °C: nucleophilic substitution
of chloride by OH- and base-catalyzed amide hydrolysis. A

4746 J. Agric. Food Chem., Vol. 54, No. 13, 2006
Carlson et al.
Scheme 5a
a Modified from ref 42.
(BAC2; base-catalyzed acyl cleavage, bimolecular), the amide
group is attacked by a hydroxide ion to form an ionic
intermediate that subsequently cleaves to form the products
shown in Scheme 5. In the second reaction, whose rate is
second-order in hydroxide ion concentration (42), the ionic
intermediate formed in the first reaction loses a proton prior to
formation of the products. Biechler and Taft used data for the
reaction of methylchlor at hydroxide concentrations varying
from 0.0557 to 0.557 M to calculate the two relevant rate
constants (42). Applying their results (8.8 × 10-4 M-1 s-1 and
1.8 × 10-3 M-2 s-1, respectively) to our system results in a
predicted pseudo-first-order rate constant of 8.8 × 10-3 s-1
,
which is within a factor of two of our measured value of 1.4 ×
10-2 s-1. The predicted value is dominated by the process that
is second-order with respect to hydroxide, which makes up 80%
of the overall rate constant. Although Biechler and Taft claimed
that ionic strength had little effect on reaction rate (42), these
rate constants are only strictly applicable to an ionic strength
of 0.557.
Figure 4. Example time courses for reaction in 2 N NaOH at 25 °C for
(a) propachlor (
for the reaction with propachlor is for isopropylaniline (
lines and triangles ( ) represent mass balances on parent compounds
and products shown, solid lines represent model fits assuming pseudo-
first-order transformation to one (methylchlor) or two (propachlor) stable
products, and error bars represent 95% confidence intervals.
b
) and (b) methylchlor (
O
). Note that the secondary y-axis
[
) only. Dashed
Aside from methylchlor, the other chloroacetamides reacted
primarily, if not exclusively, via nucleophilic substitution under
basic conditions, with rate constants that varied over nearly 2
orders of magnitude (Table 2). Time courses for selected
chloroacetamides are shown in semilogarithmic form in Figure
5, and the mass spectra of the hydroxy-substituted products are
shown in Figure S9 of the Supporting Information. For the
alkoxyalkyl-substituted chloroacetamides, small amounts of
amide hydrolysis products were only observed long after the
substitution reactions were complete.
Relative SN2 reactivity trends for the reactions of different
chloroacetamides with a variety of nucleophiles in aqueous
solution tend to be largely independent of the identity of the
nucleophile (Table 3). For example, the relative reactivities of
chloroacetamides toward hydroxide generally parallel those
observed in the reactions of these compounds with sulfur
nucleophiles (14, 22, 23), with the order of reactivity being
propachlor > alachlor > metolachlor. Differences in reactivity
among the different compounds were found to be smaller for
reactions with glutathione than for reactions with smaller
nucleophiles, perhaps because the latter are less likely to
encounter adverse steric interactions. Although these reactivity
trends are based on a limited set of data, their consistency across
different nucleophiles indicates that each chloroacetamide may
have an inherent susceptibility to nucleophilic substitution that
remains relatively independent of nucleophile identity.
The rate of chlorine displacement from a chloroacetamide
may be related to the distribution of the molecule between its
cis and trans forms at equilibrium (Scheme 6). The trans
2
time course for propachlor (Figure 4a) shows the appearance
of the products of both reactions, hydroxypropachlor (2-
hydroxy-N-isopropylacetanilide) and N-isopropylaniline. Pro-
pachlor was the only chloroacetamide for which both reactions
appeared to take place concurrently. Pseudo-first-order rate
constants for these reactions are given in Table 2. Longer term
experiments showed that the hydrolysis of the amide group of
hydroxypropachlor is sufficiently slow as to be negligible over
the time frame shown in Figure 4a.
Methylchlor reacted via amide hydrolysis to form N-methyl-
aniline so rapidly (with a half-life of less than 50 s) that no
substitution product was observed (Figure 4b). The rate constant
(Table 2) for this reaction was nearly 4 orders of magnitude
greater than the corresponding amide hydrolysis rate constant
for propachlor. As suggested earlier for the acidic reactions,
this effect appears to reflect (at least in part) the greater tendency
of the isopropyl group to block access to the reaction site at
the amide carbon, relative to a methyl group in the same
location.
The alkaline hydrolysis of amides has been postulated to
involve two preequilibrium steps as shown (Scheme 5), resulting
in two reactive intermediates and two rate constants. For the
first reaction, whose rate is first-order with respect to hydroxide

Hydrolysis of Chloroacetamide Herbicides
J. Agric. Food Chem., Vol. 54, No. 13, 2006 4747
Table 4. Estimated Amount of Hydrolysis Products Observed after
Incubation in Distilled, Deionized H2Oa
length of
incubation
(days)
amide
hydrolysis
product (%)
substitution
product (%)
morpholinone
product (%)
chloroacetamide
N-alkyl substituted
methylchlor
propachlor
521
759
1
14
1
trace
N-alkoxymethyl substituted
alachlor
600
4
acetochlor
butachlor
600
600
3
0.1
N-alkoxyethyl substituted
pretilachlor
600
1
6
dimethachlor
dimethenamid
metolachlor
521
600
1052
2
0.2
1
0.1
0.1
8
Figure 5. Selected time courses for reactions of chloroacetamides in 2
N
NaOH at 25
°
C, including metolachlor
(
[
), dimethenamid
(O),
dimethachlor ( ), acetochlor (
2
]
), and propachlor (9
). As described in
a Reactors were stored in the dark; the pH was not controlled but was measured
at the end of the experiment and found to be 5.5. Amounts given are percents
the text, propachlor reacts under these conditions via concurrent
substitution and amide hydrolysis, while only substitution products were
observed for the other chloroacetamide herbicides. Solid lines represent
linear regressions to the data shown.
∼
of total observed mass estimated from total ion chromatogram (TIC) peak areas,
assuming mass response for the product similar to the parent (this approach
generally results in a significant underestimation of concentrations for hydroxy-
substituted chloroacetamides). The balance of the mass is the parent. In a few
cases, values are corrected for impurities (<1%) observed in initial samples after
3 days of incubation. Rate constants should not be extrapolated from data in this
table.
Table 3. Relative Reactivity for Substitution Reactions of
Chloroacetamidesa
nucleophile and ref
-
-
2
-
2-
OH
b
HS
Sn
S2O3
glutathionec
(23)
predominant configuration (43, 45). Previous work has shown
that the cis to trans interconversion rate is on the order of
seconds for alachlor and acetochlor (46) and thus on a time
scale that is much shorter than the rate of hydroxide substitution.
In such a case, the Winstein-Holness equation (47) can provide
an expression for the observed rate constant (kobs):
chloroacetamide
(22)
(22)
(14)
propachlor
acetochlor
butachlor
25
20
36
15
5.2
2.9
1.7
0.9
1.9
2.0
1.4
8.0
7.9
7.7
5.8
4.7
1.8
1
alachlor
6.0
1
2.0
1
7.1
pretilachlor
dimethachlor
dimethenamid
metolachlor
kobs ) k1 ‚ xcis + k2 ‚ xtrans
(1)
1
1
a Normalized to the rate constant for metolachlor for each nucleophile. b This
study. c Estimate of relative reactivity based on extent of reaction after 3 h in the
absence of glutathione transferase.
where xcis and xtrans are the mole fractions of the chloroacetamide
molecule that are present in the cis and trans conformations,
respectively. If the contribution of the trans conformation to
substitution reactivity is assumed to be negligible (k2 = 0) and
the reactivities of different chloroacetamides in the cis confor-
mation are approximately the same (similar k1 values), then the
overall reaction rates of chloroacetamides would vary directly
with the proportion of the molecules that are present in the cis
form (xcis). Research has shown that the cis:trans ratios, which
are likely to be at least somewhat dependent on the solvent,
vary slightly for alachlor, acetochlor, and metolachlor in various
organic solvents, ranging from <1 to 8% cis (46). Variations
in the cis:trans ratio might, therefore, be sufficient to account
for the observed 8-fold variation in the observed rates of
nucleophilic substitution reactions with hydroxide.
Scheme 6
Reactions under Environmentally Relevant Conditions.
It is difficult to extrapolate the observed rate constants in Table
2 to an environmentally relevant pH because the relative
contributions of the reactions that are first-order and second-
order with respect to OH-, discussed above, are not known for
all of the chloroacetamides. Moreover, reaction with the neutral
species (H2O) might dominate the overall transformation rate
at neutral pH. The nonideal conditions of high ionic strength
solutions also affect the rate constants. For instance, we found
conformation is much less reactive toward substitution at the
chlorine because of hindrance to backside attack imposed by
the aromatic ring. Haloacetamides with the carbonyl group trans
to the aromatic ring have been shown to be 250-40000 times
less reactive toward nucleophilic substitution than the cis
conformer (43, 44), even though the trans isomer is the

4748 J. Agric. Food Chem., Vol. 54, No. 13, 2006
Carlson et al.
Scheme 7
a high degree of uncertainty and thus should not be used to
calculate rate constants.
Although the rate constants in Table 2 cannot be used to
predict environmental persistence at neutral pH, extrapolations
can still provide a useful perspective. Using metolachlor as an
example, we computed an upper limit estimate for the second-
order rate constant for an SN2 reaction, assuming solely first-
order kinetics with respect to OH-. On the basis of the rate
constant in Table 2, for the reaction with hydroxide, we estimate
that only 0.00006% of the parent would react to form hy-
droxymetolachlor at pH 5.5 after 3 years at room temperature
(approximately 25 °C). This corresponds to a half-life for
metolachlor on the order of 3 million years for this pathway.
Likewise, estimates of the amount of metolachlor undergoing
transformation via the acid-catalyzed pathway are approximately
0.0001-0.0002%; the proportion of the parent compound that
reacts to form the morpholinone product by this route would
be even smaller. Table 4 clearly shows much larger amounts
of product formation than these calculations suggest. The
products observed during this set of experiments are therefore
likely to be the result of neutral reactions. The formation of the
hydroxy-substituted and amide hydrolysis products can be easily
explained by reaction with H2O as a nucleophile. The formation
of the morpholinone derivatives would be a more surprising
result, but one possible concerted mechanism for these reactions
is depicted in Scheme 7.
The unexpected presence of the morpholinone products in
the long-term near-neutral pH experiments highlights the
importance of a systematic evaluation of the reactivity of
chloroacetamides, even under reaction conditions that are
substantially different from those encountered in the hydrologic
system. The high-temperature, high-concentration acid- and
base-catalyzed hydrolysis studies formed several products that
were also detected for chloroacetamide hydrolysis under envi-
ronmentally relevant conditions. These observed products are
rarely considered in investigations of the occurrence of chlo-
roacetamide degradates in the environment. The results pre-
sented here suggest that these degradates may form in substantial
quantities, especially under conditions of low biological activity
and long hydraulic residence timessconditions that are com-
monly encountered in groundwater.
Figure 6. Total ion chromatogram of hexane extract of aqueous solution
of pretilachlor after 600 days of incubation in deionized water at pH
∼
5.5.
The EI mass spectra of the two degradates identified (hydroxypretilachlor
and the morpholinone derivative) are shown; all other peaks are present
in solvent blanks. The insert in the chromatogram shows an expanded
version for retention times between 17.5 and 19 min.
that the reaction of propachlor in 1 N NaOH was nearly 30%
slower when the ionic strength was doubled (using NaClO4).
Additional experiments were therefore carried out for a period
of 2-3 years in deionized water at a pH between 5 and 6
(measured at the end of reaction). Three samples (including an
initial sample) were taken, and the hexane extracts were
examined to monitor the appearance of nonionized hydrolysis
products. The results from the analysis of the final sample for
each compound are shown in Table 4. For seven of the nine
chloroacetamides, the hydroxy-substituted product was observed
to accumulate in significant quantities (g1% by the final
measurement). For the N-alkyl-substituted chloroacetamides, the
amide hydrolysis product was also observed. Finally, for the
N-alkoxyethyl-substituted chloroacetamides, morpholinone de-
rivatives were also observed. In the case of the metolachlor
derivative, this was confirmed by comparison with an authentic
standard. No N-dealkylation products were observed for any
chloroacetamide.
ACKNOWLEDGMENT
We are grateful to Michelle Hladik and Jonie Hsiao for
assistance with synthesis and NMR and Tanya Oxenberg for
assistance with the acridine orange method.
As an illustration of the compounds produced by these
reactions, Figure 6 shows a total ion chromatogram for
pretilachlor, as well as the mass spectra for the two products
observed. The values in Table 4 represent rough estimates of
product concentrations based on the areas of relatively small,
often tailing peaks of compounds for which reference materials
could not always be obtained. As a result, these estimates have
Supporting Information Available: Procedures used to
synthesize two chloroacetamide degradates and data pertaining
1
to their mass and NMR spectra. Mass spectra of hydrolysis
products observed in this study as well as a scheme outlining
proposed pathways in acid hydrolysis of N-alkoxyethyl-
substituted chloroacetamides. This material is available free of
charge via the Internet at http://pubs.acs.org.

Hydrolysis of Chloroacetamide Herbicides
J. Agric. Food Chem., Vol. 54, No. 13, 2006 4749
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Received for review December 8, 2005. Revised manuscript received
April 4, 2006. Accepted April 5, 2006. This material is based upon work
supported under a National Science Foundation Research Fellowship,
an American Water Works Association Abel Wolman Fellowship, and
an Academic Rewards for College Scientists (ARCS) Fellowship
awarded to D.L.C. Additional support for this research was provided
by the National Science Foundation (NSF, #CHE-0089168) as part of
the Collaborative Research Activities in Environmental Molecular
Science (CRAEMS) project in Environmental Redox-Mediated Deha-
logenation Chemistry at Johns Hopkins University. Early stages were
funded by an NSF Young Investigator Award (Grant BES-9457260)
to A.L.R. Additional support for K.D.T. was provided by a Provost’s
Undergraduate Research Award and by a Woodrow Wilson under-
graduate fellowship.
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